title: Acute simvastatin inhibits K ATP channels of porcine coronary artery myocytes.
abstract: BACKGROUND
  Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) consumption provides beneficial effects on cardiovascular systems. However, effects of statins on vascular KATP channel gatings are unknown.
  
  
  METHODS
  Pig left anterior descending coronary artery and human left internal mammary artery were isolated and endothelium-denuded for tension measurements and Western immunoblots. Enzymatically-dissociated/cultured arterial myocytes were used for patch-clamp electrophysiological studies and for [Ca(2+)]i, [ATP]i and [glucose]o uptake measurements.
  
  
  RESULTS
  The cromakalim (10 nM to 10 µM)- and pinacidil (10 nM to 10 µM)-induced concentration-dependent relaxation of porcine coronary artery was inhibited by simvastatin (3 and 10 µM). Simvastatin (1, 3 and 10 µM) suppressed (in okadaic acid (10 nM)-sensitive manner) cromakalim (10 µM)- and pinacidil (10 µM)-mediated opening of whole-cell KATP channels of arterial myocytes. Simvastatin (10 µM) and AICAR (1 mM) elicited a time-dependent, compound C (1 µM)-sensitive [(3)H]-2-deoxy-glucose uptake and an increase in [ATP]i levels. A time (2-30 min)- and concentration (0.1-10 µM)-dependent increase by simvastatin of p-AMPKα-Thr(172) and p-PP2A-Tyr(307) expression was observed. The enhanced p-AMPKα-Thr(172) expression was inhibited by compound C, ryanodine (100 µM) and KN93 (10 µM). Simvastatin-induced p-PP2A-Tyr(307) expression was suppressed by okadaic acid, compound C, ryanodine, KN93, phloridzin (1 mM), ouabain (10 µM), and in [glucose]o-free or [Na(+)]o-free conditions.
  
  
  CONCLUSIONS
  Simvastatin causes ryanodine-sensitive Ca(2+) release which is important for AMPKα-Thr(172) phosphorylation via Ca(2+)/CaMK II. AMPKα-Thr(172) phosphorylation causes [glucose]o uptake (and an [ATP]i increase), closure of KATP channels, and phosphorylation of AMPKα-Thr(172) and PP2A-Tyr(307) resulted. Phosphorylation of PP2A-Tyr(307) occurs at a site downstream of AMPKα-Thr(172) phosphorylation.
authors.affiliation: The Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia.
authors.forename: Sai Wang
authors.initials: SW
authors.lastname: Seto
authors.forename: Alice Lai Shan
authors.initials: AL
authors.lastname: Au
authors.forename: Christina Chui Wa
authors.initials: CC
authors.lastname: Poon
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Rachel Wai Sum
authors.initials: RW
authors.lastname: Li
authors.forename: John Hok Keung
authors.initials: JH
authors.lastname: Yeung
authors.forename: Siu Kai
authors.initials: SK
authors.lastname: Kong
authors.forename: Sai Ming
authors.initials: SM
authors.lastname: Ngai
authors.forename: Song
authors.initials: S
authors.lastname: Wan
authors.forename: Ho Pui
authors.initials: HP
authors.lastname: Ho
authors.forename: Simon Ming Yuen
authors.initials: SM
authors.lastname: Lee
authors.forename: Maggie Pui Man
authors.initials: MP
authors.lastname: Hoi
authors.forename: Shun Wan
authors.initials: SW
authors.lastname: Chan
authors.forename: George Pak Heng
authors.initials: GP
authors.lastname: Leung
authors.forename: Yiu Wa
authors.initials: YW
authors.lastname: Kwan
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054086:KATP Channels; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; D000263:Adenylate Kinase; D054648:Protein Phosphatase 2; C031143:AICA ribonucleotide; D005947:Glucose